Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by rapid cognitive and functional decline in patients diagnosed with the disease. In the early stages of the disease the patients generally suffer from mild cognitive impairment (MCI) that can convert over time to full blown AD. The disease broadly falls into two categories: a) late onset AD, that occurs generally in subjects 65 years or older and that is often correlated to numerous risk factors including presence of an APOE ε4 allele; and b) early onset AD, develops early on in subjects between 30 and 60 years of age and is generally associated with familial Alzheimer's disease (FAD) mutations in the amyloid precursor protein (APP) gene or in the presenilin gene. In both types of disease, the pathology is the same but the abnormalities tend to be more severe and widespread in cases beginning at an earlier age.
AD is generally characterized by at least two types of lesions in the brain, senile plaques composed of the Aβ peptide (and other components, typically at lower concentrations than the Aβ peptide) and neurofibrillary tangles composed primarily of intracellular deposits of microtubule associated tau protein (especially hyperphosphorylated tau). Measurement of the levels of Aβ peptide and Tau/phosphorylated Tau in cerebrospinal fluid (CSF) along with imaging analysis and cognitive/functional tests can be used clinically to determine progression of the disease and conversion to full-blown AD.
Alzheimer's disease (AD) has been viewed largely as a disease of toxicity, mediated by the collection of a small peptide (the Aβ peptide) that damages brain cells by physical and chemical properties, such as the binding of damaging metals, reactive oxygen species production, and direct damage to cell membranes. While such effects of Aβ have been clearly demonstrated, they do not offer a physiological role for the peptide.
In this regard it is noted that in therapies that showed marked reduction of β-amyloid levels in AD, limited to no cognitive improvement was observed. This was unexpected by much of the research community, as AD has been largely viewed as a disease of chemical and physical toxicity of β-amyloid (e.g., generation of reactive oxygen species, metal binding, etc.).
Recent research using transgenic mice have demonstrated that blockage of the C-terminal cleavage of amyloid precursor protein (“APP”) at aspartic acid residue (D664 of APP695) intracellularly leads to abrogation of the characteristic pathophysiological abnormalities and behavioral symptoms associated with Alzheimer's disease. The methods described herein are based, in part, on the identification of molecules that modulate the processing of APP from the pro-AD fragments (e.g., sAPPβ, Aβ, Jcasp and C-31 (Jcasp and C-31 fragment levels can be determined by measuring the levels of APPneo—a full length fragment of APP without the C-terminal 31 amino acids)) to the anti-AD fragments (e.g., sAPPα, p3 and AICD).